| 1. |
- Bry, Kristina, 1953, et al.
(författare)
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Mechanisms of inflammatory lung injury in the neonate: lessons from a transgenic mouse model of bronchopulmonary dysplasia.
- 2010
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Ingår i: Seminars in perinatology. - : Elsevier BV. - 1558-075X .- 0146-0005. ; 34:3, s. 211-21
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Forskningsöversikt (refereegranskat)abstract
- The role of inflammation in the pathogenesis of bronchopulmonary dysplasia (BPD) is not well understood. By using a transgenic mouse expressing the inflammatory cytokine interleukin (IL)-1beta in the lung, we have shown that perinatal expression of IL-1beta causes a BPD-like illness in infant mice. We have used this model to identify mechanisms by which inflammation causes neonatal lung injury. Increased matrix metalloproteinase (MMP)-9 activity is associated with BPD. MMP-9 deficiency worsens alveolar hypoplasia in IL-1beta-expressing newborn mice, suggesting that MMP-9 has a protective role in neonatal inflammatory lung injury. The beta6 integrin subunit, an activator of transforming growth factor-beta, is involved in adult lung disease. Absence of the beta6 integrin subunit improves alveolar development in IL-1beta-expressing mice, suggesting that the beta6 integrin subunit is a pathogenetic factor in inflammatory lung disease in the newborn. The authors of clinical studies who have examined maternal inflammation as a risk factor for BPD have found variable results. We have shown that maternal IL-1beta production preceding fetal IL-1beta production prevents lung inflammation, alveolar hypoplasia, and airway remodeling in newborn IL-1beta-expressing mice. Thus, maternal inflammation may protect the newborn lung against subsequent inflammatory injury. In contrast, when maternal and fetal production of IL-1beta are induced simultaneously, the development of IL-1beta-induced lung disease in the newborn is not prevented.
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| 2. |
- Bäckström, Erica, 1980, et al.
(författare)
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Developmental Stage is a Major Determinant of Lung Injury in a Murine Model of Bronchopulmonary Dysplasia.
- 2011
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Ingår i: Pediatric research. - 1530-0447. ; 69:4, s. 312-318
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Tidskriftsartikel (refereegranskat)abstract
- Bronchopulmonary dysplasia (BPD) is a common inflammatory lung disease in premature infants. To study the hypothesis that the sensitivity of the lung to inflammatory injury depends on the developmental stage, we studied postnatal lung development in transgenic mice expressing human interleukin-1β (hIL-1β) in the lungs during the late canalicular-early saccular, saccular, or late saccular-alveolar stage. Overexpression of hIL-1β in the saccular stage caused arrest in alveolar development, airway remodeling, and goblet cell hyperplasia in the lungs as well as poor growth and survival of infant mice. Overexpression of hIL-1β during the late canalicular-early saccular stage did not adversely affect lung development, growth, or survival of the pups. Mice expressing hIL-1β from the late saccular to alveolar stage had smaller alveolar chord length, thinner septal walls, less airway remodeling and mucus metaplasia, and better survival than mice expressing hIL-1β during the saccular stage. Human IL-1β overexpression in the saccular stage was sufficient to cause a BPD-like illness in infant mice, whereas the lung was more resistant to hIL-1β-induced injury at earlier and later developmental stages. ABBREVIATIONS:
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| 3. |
- Bäckström, Erica, 1980
(författare)
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Influence of inflammation and of stage of lung development on the development of neonatal lung injury
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bronchopulmonary dysplasia (BPD) is a major cause of mortality and long-term morbidity in prematurely born infants. Pulmonary inflammation, and abnormal alveolar and vascular development of the lung are histological characteristics of BPD. Interleukin (IL)-1β is a central cytokine in inflammation. Increased concentration of IL-1β in amniotic fluid or postnatally in the lungs of newborn infants is associated with the development of BPD. Bitransgenic mice expressing human (h)IL-1β in the lung epithelium develop a BPD-like illness. The aims of this thesis were to study the development of hIL-1β-induced lung disease in this transgenic mouse model in order to find factors regulating the development of the disease and to analyze gastric fluid in order to identify premature infants who are at high risk of developing BPD. Since preterm labor is often preceded by intrauterine infection, the majority of infants born at less than 30 weeks of gestation have been exposed to antenatal inflammation. To study the effect of maternal inflammation on fetal inflammatory responses, hIL-1β expression was induced in pregnant dams and their hIL-1β-expressing offspring were compared to those of control dams. In bitransgenic dams, the production of hIL-1β starts before the fetuses start producing hIL-1β. The results show that maternal hIL-1β production preceding fetal hIL-1β production causes silencing of inflammatory genes in the lungs of bitransgenic offspring and protects them against hIL-1β-induced lung injury. The mammalian lung undergoes five distinct developmental stages, the embryonic, the pseudoglandular, the canalicular, the saccular, and the alveolar stage. Children developing BPD are typically born in the early saccular stage. Expression of hIL-1β was induced in fetal and newborn mice at different time points in order to study the sensitivity of the lung to hIL-1β-induced injury during the different developmental stages. The results show that hIL-1β production in the lungs during the mid-saccular stage, but not in the late canalicular-early saccular or late saccular-alveolar stages, is sufficient to cause a BPD-like illness with abnormal lung development, inflammation, and increased mortality. Usually tracheal aspirates are used to detect inflammation in the newborn lung. Obtaining tracheal aspirates from premature infants requires intubation, an invasive procedure that may promote the development of BPD. Gastric aspirate samples can be retrieved from premature infants at the time of routine placement of a nasogastric tube shortly after birth. The results show that levels of inflammatory proteins in the gastric aspirates are strongly increased in fetuses exposed to clinical chorioamnionitis and are associated with the development of BPD. These results suggest that gastric aspirate can be used instead of more invasive methods to assess the exposure of premature infants to inflammation and to assess the impact of perinatal inflammation on neonatal outcome.
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| 4. |
- Bäckström, Erica, 1980, et al.
(författare)
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Maternal IL-1beta production prevents lung injury in a mouse model of bronchopulmonary dysplasia.
- 2010
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Ingår i: American journal of respiratory cell and molecular biology. - 1535-4989. ; 42:2, s. 149-60
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about the influence of maternal inflammation on neonatal outcome. Production of IL-1beta in the lungs of newborn infants is associated with bronchopulmonary dysplasia. Using bitransgenic (bi-TG) mice in which human (h) IL-1beta is expressed with a doxycycline-inducible system controlled by the Clara cell secretory protein promoter, we have shown that hIL-1beta expression causes a bronchopulmonary dysplasia-like illness in infant mice. To study the hypothesis that maternal hIL-1beta production modifies the response of the newborn to hIL-1beta, doxycycline was administered to bi-TG and control dams from Embryonic Day 0, inducing production of hIL-1beta by the bi-TG dams before hIL-1beta production started in their bi-TG fetuses, or from Embryonic Day 15, inducing simultaneous production of hIL-1beta by both the bi-TG dams and their bi-TG fetuses. In addition to the lungs, hIL-1beta was expressed at low levels in the uteri of bi-TG dams. Maternal inflammation preceding fetal inflammation increased the survival and growth of hIL-1beta-expressing pups, enhanced alveolarization, and protected the airways against remodeling and goblet cell hyperplasia. Maternal hIL-1beta production preceding fetal hIL-1beta production caused silencing of several inflammatory genes, including CXC and CC chemokines, murine IL-1beta, serum amyloid A3, and Toll-like receptors 2 and 4, and suppressed the expression of chitinase-like lectins Ym1 and Ym2 in the lungs of infant mice. Maternal inflammation protects the newborn against subsequent hIL-1beta-induced lung inflammation and injury. In contrast, induction of hIL-1beta production simultaneously in bi-TG dams and their fetuses offered no protection against inflammatory lung disease in the neonate.
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| 5. |
- Hogmalm, Anna, 1981, et al.
(författare)
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Role of CXC Chemokine Receptor-2 in a Murine Model of Bronchopulmonary Dysplasia.
- 2012
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Ingår i: American journal of respiratory cell and molecular biology. - 1535-4989. ; 47:6, s. 746-758
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Tidskriftsartikel (refereegranskat)abstract
- The contribution of neutrophils and CXC chemokines to the pathogenesis of bronchopulmonary dysplasia (BPD) is not well defined. Transgenic expression of interleukin (IL)-1β in the pulmonary epithelium causes lung inflammation and disrupts alveolar development in infant mice. To study the hypothesis that CXC chemokine receptor 2 (CXCR2) is a mediator of inflammatory lung injury, we compared lung development in IL-1β-expressing mice with wild-type (IL-1β/CXCR2+/+) or null (IL-1β/CXCR2-/-) CXCR2 loci. CXCR2 deficiency abolished the transmigration of neutrophils into the alveolar lumen in IL-1β-expressing mice but did not alter the number of neutrophils in the parenchyma. Deletion of CXCR2 increased the alveolar chord length and reduced the survival of the mice when IL-1β was expressed from the pseudoglandular to the alveolar stages. The capillary configuration was highly abnormal, in both IL-1β/CXCR2+/+ and IL-1β/CXCR2-/- lungs, but in very different ways. The cellular area of the parenchyma and the total capillary area of IL-1β/CXCR2+/+ and IL-1β/CXCR2-/- were smaller than those of control/CXCR2+/+ and control/CXCR2-/- mice, but the ratio of capillary area to cellular area was similar in all four genotypes. When IL-1β was expressed during the saccular stage, IL-1β/CXCR2-/- mice had smaller alveolar chord length and better survival than IL-1β/CXCR2+/+ mice. Independent of the timing of IL-1β expression, IL-1β increased alveolar septal thickness in mice with wild-type CXCR2 loci but not in CXCR2 null mice. Depending on the developmental stage at the time of the inflammatory insult, inhibition of the CXCR2-pathway may have opposite effects on alveolar septation in the neonatal lung.
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| 6. |
- Stichel, H, et al.
(författare)
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Inflammatory cytokines in gastric fluid at birth and the development of bronchopulmonary dysplasia
- 2011
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Ingår i: Acta paediatrica (Oslo, Norway : 1992). - : Wiley. - 1651-2227 .- 0803-5253. ; 100:9, s. 1206-1212
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To assess whether the levels of inflammatory and anti-inflammatory proteins in gastric fluid of premature infants shortly after birth are associated with the development of bronchopulmonary dysplasia (BPD). Methods: Gastric fluid retrieved within 1h of birth of premature infants (gestational age <29weeks) was analysed for interleukin (IL)-8, growth-related oncogene (Gro)-α, epithelial cell-derived neutrophil-activating peptide (ENA)-78, IL-1β and Clara cell secretory protein with ELISA. Results: Of 51 enrolled infants, 86% had BPD. Of these, 54% had mild BPD, 30% had moderate BPD and 16% had severe BPD. Clinical chorioamnionitis was associated with high levels of IL-8, Gro-α, Epithelial cell-derived neutrophil-activating peptide-78 (ENA-78) and IL-1β in gastric fluid. Gastric fluid levels of IL-8, Gro-α, ENA-78 and IL-1β were higher in infants with moderate or severe BPD than in those with no or mild BPD. Ligation of the patent ductus arteriosus was associated with the development of moderate or severe BPD. These associations were no longer significant after adjustment for gestational age. Conclusion: The levels of inflammatory mediators in gastric fluid samples retrieved soon after birth from intubated or nonintubated infants can be used to assess the infants' perinatal exposure to inflammatory mediators and its association with neonatal outcome.
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| 7. |
- Thomas, Richard D., et al.
(författare)
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The double electrostatic ion ring experiment : A unique cryogenic electrostatic storage ring for merged ion-beams studies
- 2011
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Ingår i: Review of Scientific Instruments. - : AIP Publishing. - 0034-6748 .- 1089-7623. ; 82:6, s. 065112-
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Tidskriftsartikel (refereegranskat)abstract
- We describe the design of a novel type of storage device currently under construction at Stockholm University, Sweden, using purely electrostatic focussing and deflection elements, in which ion beams of opposite charges are confined under extreme high vacuum cryogenic conditions in separate rings and merged over a common straight section. The construction of this double electrostatic ion ring experiment uniquely allows for studies of interactions between cations and anions at low and well-defined internal temperatures and centre-of-mass collision energies down to about 10 K and 10 meV, respectively. Position sensitive multi-hit detector systems have been extensively tested and proven to work in cryogenic environments and these will be used to measure correlations between reaction products in, for example, electron-transfer processes. The technical advantages of using purely electrostatic ion storage devices over magnetic ones are many, but the most relevant are: electrostatic elements which are more compact and easier to construct; remanent fields, hysteresis, and eddy-currents, which are of concern in magnetic devices, are no longer relevant; and electrical fields required to control the orbit of the ions are not only much easier to create and control than the corresponding magnetic fields, they also set no upper mass limit on the ions that can be stored. These technical differences are a boon to new areas of fundamental experimental research, not only in atomic and molecular physics but also in the boundaries of these fields with chemistry and biology. For examples, studies of interactions with internally cold molecular ions will be particular useful for applications in astrophysics, while studies of solvated ionic clusters will be of relevance to aeronomy and biology.
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